L11 Flashcards
Which receptors are responsible for T cell adhesion?
LFA on T cell - ICAM on APC
- Integrins
CD4 a little
What receptors are responsible for T cell signal transduction?
CD3 & weird squiggly receptors with ITAM
Some CD4
What is the concept of inside-out signaling for T cells?
Chemokine or TCR binding
- Create conformation change - ↑integrin receptor affinity
- Cluster integrin receptors around TCRs
NET: stronger adhesion of APC & T cell –> stronger TCR signaling
What cytokine is important for T cell costimulation?
IL2 - T cell differentiation and proliferation
Signal 1 + 2 = T cell activation
IL2 production AND
+ alpha subunit to IL2-R -> high affinity receptor –> respond stronger to IL2 produced
Which receptors are inhibitory of T cells?
T cell - APC
PD 1 - PD
CTLA4 - B7
Where do you usually find CTLA4 receptors in a resting T cell? What happens when T cell activated?
Inside cell in vesicles T cell activation: - Move to surface - Interact with B7 with higher affinity - Recruits ITIMs
What are T cell microclusters?
The idea that TCRs can’t signal transduce
Instead, they recruit all needed molecules into a cluster underneath
Explain TCR signal transduction.
TCR binds
Lck +P to ITAMs on CD3 & weird squiggly
Recruits ZAP70
What are the 3 goal TFs of the TCR signaling cascade? What is their communal function?
NA-FT
NFkB
AP1
All ↑ IL 2 for T cell differentiation and proliferation
How do T cells make NA-FT?
Lck ZAP 70 IP3 ↑[Ca2+] Calcineurin
How do T cells make NFkB?
Lck
ZAP 70
PKC
NFkB
How do T cells make AP1?
Lck ZAP70 RAS signaling MAP kinase AP1
What is methotrexate?
Drug that blocks T cell replication
What is belatacept?
Drug blocks signal 2: B7-CD28
No T cell development
What is cyclosporin? What is the genetic variant for metabolism?
Inactivates calcineurin
CYP3A5
What is basiliximab?
Ab against IL2-R
No clonal expansion of T cells
What is sirolimus?
Blocks IL2-R signaling
What chemokine receptor directs cells into the B zone of lymph nodes? T zone?
B zone: CXCR5
T zone: CCR7
What chemokine directs T cells out of the lymph node into the blood?
S1P
What chemokine directs T cells out of the blood and into specific tissues?
CXCR3
What is the fxn of drug FTY720?
Blocks S1P receptor
T cells stay in lymph node
In general, tyrosine phosphatases work to decrease tyrosine kinase activity in T cell inactivation. What happens if you have mutations in your phosphatases?
Inability to regulate immune responses:
Cancer - too much T cell dampening
Autoimmunity - too little
What is activation induced cell death?
Negative regulation of T cells
FasL expressed on T cells after activation
FasL + Fas (receptor on neighboring T cells)
- Fas = TNF death receptor, works via caspases
Fas trimerizes
DNA fragmentation
What is human autoimmune lymphoproliferative syndrome (ALPS)?
Mutation in Fas
No activation induced cell death of T cells
What is CD95?
Fas receptor on T cells
What is necessary for BCR activation?
Cross linking!!!
Explain BCR signaling. What are the downstream products?
Cross link BCRs & bind TAAPA
Blk, Fyn, or Lyn +P to ITAMs on CD19 & Ig alpha/beta
SYK
Downstream products: NF-AT, NFkB, AP1
What is the negative regulation for B cells?
Ab Fc region binds BCR instead of antigen
Enacts ITIM
